Cells are continually exposed to factors, such as intracellular reactive species and environmental agents, which are capable of causing DNA damage. The potentially mutagenic consequences of DNA damage are minimized by DNA repair pathways, which are broadly characterized into three forms: base excision repair (BER), mismatch repair (MMR), and nucleotide excision repair (NER) (Wood et al., Science, 291: 1284-1289 (2001)). Deficiencies in DNA damage repair underlie the pathogenesis of cancer as well as many genetic disorders.
The gene encoding the CUL4A ubiquitin ligase (also referred to in the art as Cullin Ring Ligase 4 (CRL4) and Cullin-4A) is frequently amplified or overexpressed in a wide variety of cancer types, such as breast cancer (Chen et al., Cancer Res., 58: 3677-3683 (1998); and Melchor et al., Breast Cancer Res., 11: R86 (2009)), hepatocellular carcinoma (Yasui et al., Hepatology, 35: 1476-1484 (2002)), colon cancer, squamous cell carcinoma (Shinomiya et al., Genes Chromosomes Cancer, 24: 337-344 (1999)), adrenocortical carcinoma (Dohna et al., Genes Chromosomes Cancer, 28: 145-152 (2000)), childhood medulloblastoma (Michiels et al., J. Pediatr. Hematol. Oncol., 24: 205-210 (2002)), and primary malignant pleural mesothelioma (Hung et al., J. Cell. Mol. Med., 15(2): 350-358 (2011)).
CUL4A functions as a component of a multimeric protein complex wherein the C-terminus of CUL4A interacts with the RING finger protein Rbx1/ROC1/Hrt1 (hereinafter referred to as Rbx1) to recruit the E2 ubiquitin-conjugating enzyme, and the N-terminus of CUL4A interacts with damage-specific DNA binding protein 1 (DDB1). DDB1, in turn, acts as an adaptor, binding to DDB1, CUL4A associated factors (DCAFs), which serve as specific substrate receptors (Angers et al., Nature, 443: 590-593 (2006); He et al., Genes Dev., 20: 2949-2954 (2006); Higa et al., Nat Cell Biol., 8: 1277-1283 (2006); Jin et al., Mol. Cell, 23: 709-721 (2006); Lee and Zhou, Mol. Cell, 26: 775-780 (2007)).
While the components of the multimeric CUL4A ubiquitination complex and several cellular targets (e.g. Cdt1, c-Jun, HOXA9, DDB2, XPC, p21, E2F1, REDD1) (reviewed in Lee and Zhou, Mol. Cell., 26: 775-780 (2007)) have been identified, the physiological role of CUL4A in tumorigenesis remains largely unknown. Damage-specific DNA binding protein 2 (DDB2) has been shown to be subjected to CUL4A-dependent ubiquitination and degradation, which leads to an overall decrease in the ability to recognize DNA lesions (Chen et al., J. Biol. Chem., 276: 48175-48182 (2001); and Nag et al., Mol. Cell Biol., 21(20): 6738-47 (2001)). Other studies have shown that the cyclin-dependent kinase inhibitor p21 is also a substrate of the CUL4A ubiquitin ligase (Abbas et al., Genes Dev., 22: 2496-2506 (2008)); Cang et al., Cell, 127: 929-940 (2006); and Kim et al., Genes Dev., 22, 2507-2519 (2008)). Conditional CUL4A knockout mice exhibit increased accumulation of DDB2 and p21, resulting in both enhanced repair activity in the removal of strand-distorting DNA lesions induced by UV (e.g. cyclobutane pyrimidine dimers (CPDs) and 6,4-photoproducts (6,4-PPs)), and prolonged G1/S DNA damage checkpoint that allows additional time for the NER machinery to remove the DNA lesions (Liu et al., Mol. Cell., 34: 451-460 (2009) and U.S. Pat. No. 8,513,181). In addition, skin-specific deletion of CUL4A rendered the knockout mice resistant to UV-induced skin carcinogenesis (Liu et al., Mol. Cell., 34: 451-460 (2009)). As such, inhibiting CUL4A may be a potential therapeutic strategy for both prevention and treatment of human cancers.
There is a need for compositions and methods to inhibit CUL4A activity for the treatment of cancer. This invention provides such compositions and methods.